In response to and in anticipation of seasonal changes in natural- light, many animals manifest marked seasonal changes in physiology and behavior, such as those related to hibernation, breeding and migration. Although humans have increasingly (but far from completely) isolated themselves from the natural environment, certain individuals manifest seasonal changes in mood and behavior, though to more modest degree than in photoperiodic animals. Some patients with recurrent mood disorders develop full major depression syndromes in the fall or winter, with full remission in spring or summer, a condition called seasonal affective disorder winter type (SAD). SAD is a condition associated with an intermittent but significant impairment in occupational, academic and social functioning. Although psychosocial difficulties in fall and winter are in the immediate picture for professionals treating SAD, the biological nature of this condition is underscored by similarities in certain SAD symptoms with season-specific behavioral changes in photoperiodic mammals (environment disengagement, increased appetite, weight and sleepiness, reduced energy and reproductive drive)24, the effectiveness of timed bright light exposure in treating SAD27-30, and an extended duration in winter of nocturnal melatonin secretion in SAD patients (but not in controls) as in photoperiodic mammals1 A previous twin study on seasonality using the Seasonal Pattern Assessment Questionnaire (SPAQ) that gives a global seasonality score (GSS) has reported that the heritability of seasonality of mood is 29%% 2. The long term objective of the PI is to study precipitating and perpetuating factors in the physical, chemical and biological environment exacerbating mood disorders in predisposed individuals, and more specifically to identify trigger- vulnerability pairs for seasonal disturbances in mood and behavior. The short term objective of this project is to identify genetic variations that are associated with seasonality of mood. We will mail the SPAQ to 1800 Amish participants previously genotyped for the 500K or 1 M Affymetrics SNP chip. GSS levels, logarithm-transformed and adjusted for age and sex, will be analyzed for heritability and screened for association with SNPs using mixed model variance components to account for familial relatedness. The "top hits" will then be replicated in 1,000 Amish participants in whom DNA is immediately available. The questionnaire response rate is expected to exceed 80%, based on long standing partnership between the research team and the Amish. This study will be novel in both genetic and environmental epidemiology domains;genetically this will be the first GWAS of mood seasonality, and environmentally, the first study of seasonality of mood in a population that predominantly does not use electricity, thus, with greater exposure and tuning to natural photoperiodic changes. The project is expected to contribute to designing future studies on SAD, with prospective measurements of mood and light exposure, in interaction with emerging candidate genes. This may lead to further studies that may ultimately result in individualized treatment of SAD, as well as potentially advance our knowledge on mechanisms leading to seasonal variation in mood, behavior and cardiovascular risk factors, such as weight, cholesterol, and immune mediators, suspected to contribute to increased cardiovascular mortality in the winter. PUBLIC HEALTH RELEVANCE: Seasonal affective disorder, also called SAD /winter depression, is a serious condition that affects millions of Americans;we propose to perform obtain a score of mood seasonality in 1000 Amish subjects who had their full genome previously analyzed for another study and whose customs do not allow use of electricity reducing exposure to artificial light in winter and use of air conditioners in summer. In line with the mission of K18, This grant will help the applicant to become fluent with full genome approaches that will add a major capability to his ongoing exploration of vulnerabilities to environmental triggers in mood disorders and suicidal behavior, domains of public health priority. The study will be the first genomic study on seasonality of mood, and first seasonality study in the US in a population not using electric light.